Urate-LRRK2 interactions in Parkinson?s disease Project Summary/Abstract: Although mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common known genetic cause of Parkinson?s disease (PD), their incomplete penetrance indicates that other genetic and environmental factors play important protective roles in LRRK2 PD. Classical epidemiology studies of PD have identified molecular factors that may contribute to or protect against the underlying neurodegenerative process. Among the latter, urate an endogenous antioxidant as well as the end product of purine metabolism has emerged as a major inverse (reduced) risk factor not only for PD onset but also for its clinical progression. A convergence of these epidemiological data with laboratory evidence of its neuroprotective properties suggests that urate may be a mediator as well as a marker of favorable outcomes in idiopathic PD. New biomarker findings of lower urate levels among LRRK2 PD patients compared to people with LRRK2 mutations who have not developed PD raise the possibility that higher levels of endogenous urate contribute to the incomplete penetrance of LRRK2 mutations. The hypothesis is strengthened by evidence that urate protects dopaminergic neurons by activating the Nrf2 antioxidant response pathway, which has recently been implicated in LRRK2 pathophysiology. The current project will determine the neuroprotective potential and molecular mechanisms of urate in laboratory models and human biomarker studies of LRRK2 PD. Through its specific aims (SAs) it will characterize the neuroprotective effects of urate and their astrocyte dependence in cellular and animal models of neurodegeneration in a LRRK2+ PD (SA 1). The role of Nrf2 in the neuroprotective actions of urate and another Nrf2 activator, dimethyl fumarate (a pharmaceutical, approved for disease modification in multiple sclerosis) will be incisively addressed through a complementary set Nrf2 knockout and Nrf2 transgene rescue studies in LRRK2+ PD models (SA 2). Lastly, the interaction between urate and LRRK2 kinase activity (gauged by levels of auto-phosphorylated LRRK2) will be explored in clinical cohorts of idiopathic and LRRK2 PD (SA 3). The mechanistic and clinical insights generated by these studies may validate Nrf2 activation as a promising therapeutic strategy in LRRK2 PD, and may thereby facilitate early steps toward personalized medicine for PD. The results may also help address a growing concern over cost-effectiveness in the field of personalized medicine because Nrf2 activators are already available for clinical use. And of those poised for efficacy trials in LRRK2 PD the urate precursor inosine has been developed as a non-proprietary therapeutic with foundation and government investment. Thus the project offers realistic prospects for advancing our understanding of PD neurobiology and treatment.